HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation

• Published in: Blood Vol. 124; no. 26; pp. 3996 - 4003
• Main Authors: Petersdorf, Effie W., Gooley, Theodore A., Malkki, Mari, Bacigalupo, Andrea P., Cesbron, Anne, Du Toit, Ernette, Ehninger, Gerhard, Egeland, Torstein, Fischer, Gottfried F., Gervais, Thibaut, Haagenson, Michael D., Horowitz, Mary M., Hsu, Katharine, Jindra, Pavel, Madrigal, Alejandro, Oudshoorn, Machteld, Ringdén, Olle, Schroeder, Marlis L., Spellman, Stephen R., Tiercy, Jean-Marie, Velardi, Andrea, Witt, Campbell S., O’Huigin, Colm, Apps, Richard, Carrington, Mary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-12-2014; American Society of Hematology
• Subjects: Adolescent; Adult; Aged; Alleles; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility - immunology; HLA-C Antigens - metabolism; Humans; Leukemia - immunology; Leukemia - therapy; Male; Medicin och hälsovetenskap; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes - immunology; Myelodysplastic Syndromes - therapy; Retrospective Studies; Transplantation; Treatment Outcome; Unrelated Donors; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-09-599969

Life-threatening graft-versus-host disease (GVHD) limits the use of HLA-C-mismatched unrelated donors in transplantation. Clinicians lack criteria for donor selection when HLA-C-mismatched donors are a patient’s only option for cure. We examined the role for HLA-C expression levels to identify permissible HLA-C mismatches. The median fluorescence intensity, a proxy of HLA-C expression, was assigned to each HLA-C allotype in 1975 patients and their HLA-C-mismatched unrelated transplant donors. The association of outcome with the level of expression of patients’ and donors’ HLA-C allotypes was evaluated in multivariable models. Increasing expression level of the patient’s mismatched HLA-C allotype was associated with increased risks of grades III to IV acute GVHD, nonrelapse mortality, and mortality. Increasing expression level among HLA-C mismatches with residue 116 or residue 77/80 mismatching was associated with increased nonrelapse mortality. The immunogenicity of HLA-C mismatches in unrelated donor transplantation is influenced by the expression level of the patient’s mismatched HLA-C allotype. HLA-C expression levels provide new information on mismatches that should be avoided and extend understanding of HLA-C-mediated immune responses in human disease.
•The expression level of patient HLA-C allotypes affects GVHD and mortality after HCT from HLA-C-mismatched unrelated donors.•Transplant outcome can be improved by avoiding high-risk HLA-C-mismatched donors when no matched stem cell source is available.